Iodine/DMSO-catalyzed oxidative deprotection of N-tosylhydrazone for benzoic acid synthesis

An oxidative deprotection of tosylhyrdazones has been demonstrated to afford benzoic acids using iodine and DMSO system. This efficient oxidative deprotection protocol offers exceptional functional group toleration under mild reaction conditions without any initiators or bases. Notably, the tosylhydrazone with the heteroaryl ring or with the aryl ring having base-sensitive hydroxyl and ester functional groups smoothly afforded the corresponding benzoic acid analogues under developed conditions. Moreover, this method features short reaction times, high product yields and easy purification by avoiding column-chromatographic purification.


Introduction
N-tosylhydrazones are popular synthons in synthetic organic chemistry for constructing potent cyclic scaffolds. 1,2The synthesis of tosylhydrazones can be straightforwardly achieved in solid form via condensation of carbonyl compounds with tosylhydrazine in high yields. 3,42][13][14] The deprotection of hydrazones into corresponding carbonyl or carboxylic acid derivatives under mild conditions is a vital process in organic synthesis.The development of mild and effective methods for the deprotection of procarbonyl compounds has been of longstanding interest of organic chemists.To date, numerous conditions or catalysts such as copper(I) chloride, 15 clayfen, 16 potassium bromate, 17 quinolinium dichromate (QDC), 18 alumina-supported ammonium chlorochromate, 19 6-benzyl-4aza-1-azoniabicyclo[2.2.2]octane dichromate, 20 and Amberlyst 15 supported nitrosonium ion 21 have been reported to accomplish the deprotection of hydrazones into corresponding carbonyl compounds.Although multiple approaches for the regeneration of carbonyl compounds from oximes 11,22,23 are reported in scientic literature, only a few reports are available from tosylhydrazones, especially with mild reaction conditions.
In 2000, Bandgar and his team reported the regeneration of carbonyl compounds using hexamethylenetetramine-bromine (HMTAB) and N-bromosuccinimide (NBS) (Scheme 1a). 24Similarly, in the same year, Chandrasekhar and his team disclosed the selective cleavage of tosylhydrazone using 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ) (Scheme 1b). 25 In 2006, Movassagh and co-workers utilized K-catalyst and calcium hypochlorite for the deprotection of tosylhydrazones (Scheme 1c). 26Likewise, Jia and his group regenerated the carbonyl compounds using meta-chloroperbenzoic acid (mCPBA) (Scheme 1d). 27Despite many attempts thus far, existing methods or conditions oen suffer from various disadvantages e.g.expensive syntheses, limited substrate scope, extended reaction time, and the use of hazardous oxidants and metal ions in certain cases.Noticeably, the usage of a mild oxidation approach for the direct conversion of tosylhydrazones to corresponding carboxylic acids is still desirable.It is therefore necessary to develop new methods based on readily available oxidants and safer chemicals.In this context, iodine and DMSO system have recently received attention as mild and selective oxidizing agent.2][33][34][35][36][37][38] Carboxylic acids are the most extensively used oxidized feedstocks and are needed in large amounts as bulk chemicals in various industries, including polymers, ne chemicals, and commercial products. 399][50] In 1971, Pierre and colleagues found that benzoic acid derivatives have antisickling properties in vitro using the root extract of Fagara xanthoxyloides. 48Similarly, Elekwa and his colleagues have revealed the anti-sickling benets of p-uorobenzoic acid. 51ence, by deliberately avoiding hazardous substances, we have discovered that tosylhydrazones can undergo direct oxidative deprotection to produce benzoic acid derivatives (Scheme 1e).3][54][55][56][57][58] Herein, we report the metal and base-free deprotection of tosylhydrazones to the oxidative product of its parent aldehyde group using iodine and DMSO system with optimal conditions.

Results and discussion
The investigation started by examining the reaction conditions using tosylhydrazone 1a as the model substrate.
Initially, reaction was conducted in the DMSO without the use of iodine at 100 °C for 1 h.Unfortunately, the reaction was failed to afford the target product 2a in the absence of iodine (Table 1, entry 1).Next, we attempted to manipulate the reaction environment by adding various reagents such as NaI, TBAI, NH 4 I and KI (Table 1, entries 2-5).However, using these reagents were futile and resulted in no product formation.Further, the use of iodine reagent in catalytic amount (10 mol% or 0.1 equiv.) in DMSO afforded the needed product 2a in 30% yield (Table 1, entry 6).It indicates that the iodine reagent is essential for this conversion.Subsequently, increasing the equivalent of iodine from 0.1 equiv.to 0.5, 1.0 and 1.5 equiv.improved the reaction efficiency to provide the 2a in 56%, 78% and 87% yields, respectively (Table 1, entries 7-9).Further, elevation in temperature from 100 to 120 °C also did not have any impactful effect on the productivity of this transformation (Table 1, entry 10).Reducing reaction temperature from 100 °C to room temperature and 70 °C signicantly affected the reaction outcome, no reaction occurred at room temperature while only 60% yield of 2a was observed at 70 °C (Table 1, entries 11 and 12).Moreover, we noticed the reaction outcome by switching to the other solvents.Changing solvents from DMSO to toluene, acetonitrile (MeCN), 1,4-dioxane, water, MeOH, DMF, THF, chloroform (CHCl 3 ) and DMA was entirely ineffective and 2a was either not observed or obtained in poor yields (Table 1, entries 13-22).It suggested that DMSO has a critical role in this reaction transformation.Finally, we found that the use of 1.5 equiv. of iodine in DMSO at 100 °C was the optimum condition for the satisfactory yield of 2a.
Under optimized reaction conditions, the accessibility of the protocol was observed with the use of a range of benzaldehyde tosylhydrazones 1 (Table 2).The reaction of benzaldehyde tosylhydrazones with electron-donating substituents such as  methyl (1b), methoxy (1c, 1f), and isopropyl (1e) either at metaor para-position of aryl rings proceeded efficiently to deliver the corresponding products 2b (88%), 2c (83%), 2e (93%) and 2f (87%).It is worth mentioning that the oxidizable thiomethyl (1d) group could sustained in the optimized reaction condition to give 2d in a 96% yield.Tosylhydrazones of benzaldehyde having halogen substituents such as uoro (1g) chloro (1h) and bromo (1i) also worked well, resulting in the production of the corresponding products 2g, 2h and 2i in high yields of 92%, 85% and 89%, respectively.The strong electron-withdrawing nitro group at the para-position of tosylhydrazone 1j had little impact on the oxidative deprotection process, giving 2j a reduced yield of 65%.It was interesting to observe that other electron-withdrawing groups para-cyano (1k), nitro (1l) and ester (-COOMe; 1l 0 ) group at meta-position did not have any negative inuence on reaction outcome, providing expected products 2k, 2l and 2l 0 in excellent yields (87-93%).Furthermore, tosylhydrazones 1m and 1n with hydroxy substitutions reacted well to afford the 2m and 2n in good yields (73-88%).It is worth mentioning that tosylhydrazones with base-sensitive functional groups such as ester (1l 0 ) and hydroxy (1m and 1n) groups were well tolerated under the optimized conditions.Delightfully, the reaction of 4-methyl-N 0 -(thiophen-2ylmethylene)benzene-sulfonohydrazide (1o) showed credible reactivity to afford 2o in 93% yield.
Some of the control studies were designed to understand the mechanistic pathway (Scheme 2).Firstly, when the reaction of benzaldehyde 3 was performed under optimized reaction conditions, benzoic acid (2a) was observed only in trace amounts (Scheme 2a).Next, we speculated that in situ generated p-TSA acid might be involved as a catalyst in benzaldehyde to benzoic acid formation.Therefore, a reaction of 3 was performed with 0.5 equiv. of p-toluenesulfonic acid (p-TSA), but 2a formation was not observed.Further, we carried out the reaction mixture's LCMS analysis for the reaction of 1b under standard conditions.LCMS data suggested the generation of p-toluenesulnic acid (TsH) instead of PTSA (see the ESI †).Hence, these experiments suggested no involvement of benzaldehyde intermediate in the developed oxidative deprotection process of N-tosylhydrazone.In conclusion, we have developed a economical, and environmentally benign method for the solvent-dependent oxidation of tosylhydrazone aldehydes into carboxylic acids.This particular transformation offers noteworthy benets: (1) oxidation can be carried out without the need for an external catalyst, initiator, base, or additive; (2) the oxidation occurs under easy and mild reaction conditions, demonstrating excellent compatibility with functional groups, as shown by its ability to tolerate moisture, acid-and base-sensitive groups, as well as easily oxidizable groups.Considering these primary benets, the current procedure can be considered as an important development in the eld of oxidative deprotection of tosylhydrazones.

aTable 2
Reaction conditions: 1a (0.36 mmol), I 2 (0.54 mmol), solvent (1.5 mL), 100 °C.b Isolated yields.NR = no reaction.RT = room temperature.Oxidative deprotection of tosylhydrazones to benzoic acid derivatives a,b a Reaction conditions: 1a (0.36 mmol), I 2 (0.54 mmol), solvent (1.5 mL), 100 °C.b Isolated yields.Based on experimental outcomes and previous studies, 59-63 a plausible mechanism for the synthesis of benzoic acid is presented in Scheme 3. Firstly, N-tosylhydrazone is believed to form a nitrogen-iodine species A by electrophilic attack of iodine.Then nucleophilic attack of H 2 O molecule may lead to species B and further elimination of a HI molecule may afford species C. Tautomerization of intermediate C is likely to give species D. Finally, an attack of water molecule may lead to the formation of desired product 2 with the loss of p-toluenesulnic acid (TsH) with diimide (N 2 H 2 ) or TsH with nitrogen gas (N 2 ) and hydrogen iodide (HI).The release of p-toluenesulnic acid was conrmed by LCMS analysis (see the ESI †).

Table 1
Optimization of reaction conditions a